The present invention relates to partially sustained-release, oral pharmaceutical forms of administration in which the active substance, tramadol, is present at least partially as a compound formed in situ which has a water solubility of ≦100 mg/ml, and to processes for their preparation.
The administration of pharmacological active substances in the form of sustained-release preparations represents a therapeutic improvement for many active substances, especially analgesics. Even for pharmacological substances with a relatively short half-life in vivo, retardation of release makes it possible to provide a preparation with a long-lasting action and also, through more constant blood levels, to avoid side effects and improve the patients' observance of dosage instructions.
The release of pharmacologically active substances can be retarded e.g. by embedding in a sustained-release matrix or by coating with sustained-release film.
The retardation of the release of very readily water-soluble active substances, e.g. tramadol hydrochloride, an analgesic for controlling intense to very intense pain, with the aid of film coatings is often complex and unsatisfactory because film coatings for such active substances frequently constitute an inadequate diffusion barrier or the permeability of these film coatings changes during storage (P. B. O'Donnell, J. W. McGinity, “Mechanical Properties of Polymeric Films, Prepared from Aqueous Polymeric Dispersions in Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms”, Drugs and the Pharmaceutical Science, vol. 79, ed. J. W. McGinity, Marcel Decker, New York, Basle, Hong Kong 1997).
The manufacture of preparations with sustained-release film coatings applied water-soluble ingredients therefore requires expensive coating processes with multilayer films or time-consuming curing processes, as described in U.S. Pat. No. 5,645,858, U.S. Pat. No. 5,580,578, U.S. Pat. No. 5,681,585 or U.S. Pat. No. 5,472,712, in K. Bauer, “Coated Pharmaceutical Dosage Forms,” Medpharm Scientific Publishers, Stuttgart 1998, B. Sutter, Thesis, University of Dusseldorf, 1987, or in F. N. Christensen, Proceed. Intern. Symp. Contr. Rel. Bioact. Mater. 17, 124, 1990.
It is also possible to retard the release of pharmaceutically active substances by reducing their solubility, e.g. by forming sparingly soluble salts (H. Sucker, Pharmazeutische Technologie (Pharmaceutical Technology), Georg Thieme Verlag, Stuttgart, N.Y. 1991). In some cases, however, the use of such sparingly soluble salts in forms of administration requires very complex processes to prepare these salts.
The object of the present invention was therefore to provide pharmaceutical formulations which do not exhibit the above disadvantages.